Review of Medical Microbiology and Immunology, 13th Edition

49. Systemic Mycoses

CHAPTER CONTENTS

Introduction

Coccidioides

Histoplasma

Blastomyces

Paracoccidioides

Self-Assessment Questions

Summaries of Organisms

Practice Questions: USMLE & Course Examinations

INTRODUCTION

These infections result from inhalation of the spores of dimorphic fungi that have their mold forms in the soil. Within the lungs, the spores differentiate into yeasts or other specialized forms, such as spherules.

Most lung infections are asymptomatic and self-limited. However, in some persons, disseminated disease develops in which the organisms grow in other organs, cause destructive lesions, and may result in death. Infected persons do not communicate these diseases to others.

Important features of the systemic fungal diseases are described in Table 49–1. Systemic fungi are also called endemic fungi because they are endemic (localized) to certain geographic areas.

TABLE 49–1 Important Features of Systemic Fungal Diseases

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COCCIDIOIDES

Disease

Coccidioides immitis causes coccidioidomycosis.

Properties

C. immitis is a dimorphic fungus that exists as a mold in soil and as a spherule in tissue (Figure 49–1).

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FIGURE 49–1 Stages of Coccidioides immitisA: Arthrospores form at the ends of hyphae in the soil. They germinate in the soil to form new hyphae. If inhaled, the arthrospores differentiate into spherules. B: Endospores form within spherules in tissue. When spherules rupture, endospores disseminate and form new spherules. (Modified and reproduced with permission from Brooks GF et al. Medical Microbiology. 20th ed. Originally published by Appleton & Lange. Copyright 1995 McGraw-Hill.)

Transmission & Epidemiology

The fungus is endemic in arid regions of the southwestern United States and Latin America. People who live in Central and Southern California, Arizona, New Mexico, Western Texas, and Northern Mexico, a geographic region called the Lower Sonoran Life Zone, are often infected. In soil, it forms hyphae with alternating arthrospores and empty cells (Figure 49–2). Arthrospores are very light and are carried by the wind. They can be inhaled and infect the lungs.

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FIGURE 49–2 Coccidioides immitis—arthrospores. Barrel-shaped, rectangular arthrospores appear blue with lactophenol cotton blue stain. Arthrospores are also called arthroconidia. (Figure courtesy of Dr. Hardin, Public Health Image Library, Centers for Disease Control and Prevention.)

Pathogenesis

In the lungs, arthrospores form spherules that are large (30 μm in diameter), have a thick, doubly refractive wall, and are filled with endospores (Figure 49–3). Upon rupture of the wall, endospores are released and differentiate to form new spherules. The organism can spread within a person by direct extension or via the bloodstream. Granulomatous lesions can occur in virtually any organ but are found primarily in bones and the central nervous system (meningitis).

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FIGURE 49–3 Coccidioides immitis—spherule. Long arrow points to a spherule in lung tissue. Spherules are large thick-walled structures containing many endospores. Short arrow points to an endospore. (Figure courtesy of Dr. L. Georg, Public Health Image Library, Centers for Disease Control and Prevention.)

Dissemination from the lungs to other organs occurs in people who have a defect in cell-mediated immunity. Most people who are infected by C. immitis develop a cell-mediated (delayed hypersensitivity) immune response that restricts the growth of the organism. One way to determine whether a person has produced adequate cell-mediated immunity to the organism is to do a skin test (see later). In general, a person who has a positive skin test reaction has developed sufficient immunity to prevent disseminated disease from occurring. If, at a later time, a person’s cellular immunity is suppressed by drugs or disease, disseminated disease can occur.

Clinical Findings

Infection of the lungs is often asymptomatic and is evident only by a positive skin test and the presence of antibodies. Some infected persons have an influenzalike illness with fever and cough. About 50% have changes in the lungs (infiltrates, adenopathy, or effusions) as seen on chest X-ray, and 10% develop erythema nodosum (see later) or arthralgias. This syndrome is called “valley fever” (in the San Joaquin Valley of California) or “desert rheumatism” (in Arizona); it tends to subside spontaneously.

Disseminated disease can occur in almost any organ; the meninges (meningitis), bone (osteomyelitis), and skin (nodules) are important sites. The overall incidence of dissemination in persons infected with C. immitis is 1%, although the incidence in Filipinos and African Americans is 10 times higher. Women in the third trimester of pregnancy also have a markedly increased incidence of dissemination. Erythema nodosum (EN) manifests as red, tender nodules (“desert bumps”) on extensor surfaces such as the skin over the tibia and ulna. It is a delayed (cell-mediated) hypersensitivity response to fungal antigens and thus is an indicator of a good prognosis. There are no organisms in these lesions; they are not a sign of disseminated disease. EN is not specific for coccidioidomycosis; it occurs in other granulomatous diseases (e.g., histoplasmosis, tuberculosis, and leprosy).

In infected persons, skin tests with fungal extracts (coccidioidin or spherulin) cause at least a 5-mm induration 48 hours after injection (delayed hypersensitivity reaction). Skin tests become positive within 2 to 4 weeks of infection and remain so for years but are often negative (anergy) in patients with disseminated disease.

Laboratory Diagnosis

In tissue specimens, spherules are seen microscopically. Cultures on Sabouraud’s agar incubated at 25°C show hyphae with arthrospores (Figure 49–2). (Caution: Cultures are highly infectious; precautions against inhaling arthrospores must be taken.) In serologic tests, IgM and IgG precipitins appear within 2 to 4 weeks of infection and then decline in subsequent months. Complement-fixing antibodies occur at low titer initially, but the titer rises greatly if dissemination occurs.

Treatment & Prevention

No treatment is needed in asymptomatic or mild primary infection. Amphotericin B (Fungizone) or itraconazole is used for persisting lung lesions or disseminated disease. Ketoconazole is also effective in lung disease. If meningitis occurs, fluconazole is the drug of choice. Intrathecal amphotericin B may be required and may induce remission, but long-term results are often poor. There are no means of prevention except avoiding travel to endemic areas. Patients who have recovered from coccidioidal meningitis should receive long-term suppressive therapy with fluconazole to prevent a recurrence.

HISTOPLASMA

Disease

Histoplasma capsulatum causes histoplasmosis.

Properties

H. capsulatum is a dimorphic fungus that exists as a mold in soil and as a yeast in tissue. It forms two types of asexual spores (Figure 49–4): (1) tuberculate macroconidia, with typical thick walls and fingerlike projections that are important in laboratory identification; and (2) microconidia, which are smaller, thin, smooth-walled spores that, if inhaled, transmit the infection.

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FIGURE 49–4 Asexual spores of Histoplasma capsulatumA: Tuberculate macroconidia. B: Microconidia. (Reproduced with permission from Brooks GF et al. Medical Microbiology. 19th ed. Originally published by Appleton & Lange. Copyright 1991 McGraw-Hill.)

Transmission & Epidemiology

This fungus occurs in many parts of the world. In the United States, it is endemic in central and eastern states, especially in the Ohio and Mississippi River valleys. It grows in soil, particularly if the soil is heavily contaminated with bird droppings, especially from starlings. Although the birds are not infected, bats can be infected and can excrete the organism in their guano. In areas of endemic infection, excavation of the soil during construction or exploration of bat-infested caves has resulted in a significant number of infected individuals.

In several tropical African countries, histoplasmosis is caused by Histoplasma duboisii. The clinical picture is different from that caused by H. capsulatum. A description of the differences between African histoplasmosis and that seen in the United States is beyond the scope of this book.

Pathogenesis & Clinical Findings

Inhaled spores are engulfed by macrophages and develop into yeast forms. In tissues, H. capsulatum occurs as an oval budding yeast inside macrophages (Figures 49–5 and 49–6). The yeasts survive within the phagolysosome of the macrophage by producing alkaline substances, such as bicarbonate and ammonia, which raise the pH and thereby inactivate the degradative enzymes of the phagolysosome.

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FIGURE 49–5 Histoplasma capsulatum. Yeasts are located within the macrophage. (Reproduced with permission from Brooks GF et al. Medical Microbiology. 19th ed. Originally published by Appleton & Lange. Copyright 1991 McGraw-Hill.)

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FIGURE 49–6 Histoplasma capsulatum—yeasts within macrophages. Arrow points to a macrophage containing several purple-stained yeasts in the cytoplasm. Yeasts within macrophages can be seen in many macrophages in this specimen of spleen. (Figure courtesy of Dr. M. Hicklin, Public Health Image Library, Centers for Disease Control and Prevention.)

The organisms spread widely throughout the body, especially to the liver and spleen, but most infections remain asymptomatic, and the small granulomatous foci heal by calcification. With intense exposure (e.g., in a chicken house or bat-infested cave), pneumonia and cavitary lung lesions may become clinically manifest. Severe disseminated histoplasmosis develops in a small minority of infected persons, especially infants and individuals with reduced cell-mediated immunity, such as patients with acquired immunodeficiency syndrome (AIDS). In AIDS patients, pancytopenia and ulcerated lesions on the tongue are typical of disseminated histoplasmosis. In immunocompetent people, EN can occur (see description of EN in earlier section on Coccidioides). EN is a sign that cell-mediated immunity is active and the organism will probably be contained.

A skin test using histoplasmin (a mycelial extract) becomes positive (i.e., shows at least 5 mm of induration) within 2 to 3 weeks after infection and remains positive for many years. However, because there are many false-positive reactions (due to cross-reactivity) and many false-negative reactions (in disseminated disease), the skin test is not useful for diagnosis. Furthermore, the skin test can stimulate an antibody response and confuse the serologic tests. The skin test is useful for epidemiologic studies, and up to 90% of individuals have positive results in areas of endemic infection.

Laboratory Diagnosis

In tissue biopsy specimens or bone marrow aspirates, oval yeast cells within macrophages are seen microscopically (Figure 49–6). Cultures on Sabouraud’s agar show hyphae with tuberculate macroconidia when grown at low temperature (e.g., 25°C) and yeasts when grown at 37°C. Tests that detect a Histoplasma polysaccharide antigen by enzyme-linked immunosorbent assay (ELISA) and Histoplasma RNA with DNA probes are also useful. In immunocompromised patients with disseminated disease, tests for Histoplasma antigen in the urine are especially useful because antibody tests may be negative.

Two serologic tests are useful for diagnosis: complement fixation (CF) and immunodiffusion (ID). An antibody titer of 1:32 in the CF test with yeast phase antigens is considered to be diagnostic. However, cross-reactions with other fungi, especially Blastomyces, occur. CF titers fall when the disease becomes inactive and rise in disseminated disease. The ID test detects precipitating antibodies (precipitins) by forming two bands, M and H, in an agar-gel diffusion assay. The ID test is more specific but less sensitive than the CF test.

Treatment & Prevention

No therapy is needed in asymptomatic or mild primary infections. With progressive lung lesions, oral itraconazole is effective. In disseminated disease, parenteral itraconazole (or amphotericin B) is the treatment of choice. Liposomal amphotericin B should be used in patients with preexisting kidney damage. In meningitis, fluconazole is often used because it penetrates the spinal fluid well. Oral itraconazole is used for chronic suppression in patients with AIDS. There are no means of prevention except avoiding exposure in areas of endemic infection.

BLASTOMYCES

Disease

Blastomyces dermatitidis causes blastomycosis, also known as North American blastomycosis.

Properties

B. dermatitidis is a dimorphic fungus that exists as a mold in soil and as a yeast in tissue. The yeast is round with a doubly refractive wall and a single broad-based bud (Figures 49–7 and 49–8). Note that this organism forms a broad-based bud, whereas Cryptococcus neoformans is a yeast that forms a narrow-based bud.

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FIGURE 49–7 Blastomyces dermatitidisA: Yeast with a broad-based bud at 37°C. B: Mold with microconidia at 20°C. (Reproduced with permission from Brooks GF et al. Medical Microbiology. 19th ed. Originally published by Appleton & Lange. Copyright 1991 McGraw-Hill.)

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FIGURE 49–8 Blastomyces dermatitidis—broad-based budding yeast. Arrow points to the broad base of the budding yeast. (Figure courtesy of Dr. L. Ajello, Public Health Image Library, Centers for Disease Control and Prevention.)

Transmission & Epidemiology

This fungus is endemic primarily in eastern North America, especially in the region bordering the Ohio, Mississippi, and St. Lawrence rivers, and the Great Lakes region. Less commonly, blastomycosis has also occurred in Central and South America, Africa, and the Middle East. It grows in moist soil rich in organic material, forming hyphae with small pear-shaped conidia. Inhalation of the conidia causes human infection.

Pathogenesis & Clinical Findings

Infection occurs mainly via the respiratory tract. Asymptomatic or mild cases are rarely recognized. Dissemination may result in ulcerated granulomas of skin, bone, or other sites.

Laboratory Diagnosis

In tissue biopsy specimens, thick-walled yeast cells with single broad-based buds are seen microscopically (Figure 49–8). Hyphae with small pear-shaped conidia are visible on culture. The skin test lacks specificity and has little value. Serologic tests have little value.

Treatment & Prevention

Itraconazole is the drug of choice for most patients, but amphotericin B should be used to treat severe disease. Surgical excision may be helpful. There are no means of prevention.

PARACOCCIDIOIDES

Disease

Paracoccidioides brasiliensis causes paracoccidioidomycosis, also known as South American blastomycosis.

Properties

P. brasiliensis is a dimorphic fungus that exists as a mold in soil and as a yeast in tissue. The yeast is thick-walled with multiple buds, in contrast to B. dermatitidis, which has a single bud (Figures 49–9 and 49–10).

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FIGURE 49–9 Paracoccidioides brasiliensis. Note the multiple buds of the yeast form of Paracoccidioides, in contrast to the single bud of Blastomyces.

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FIGURE 49–10 Paracoccidioides—yeasts with multiple buds resembling a “ship captain’s wheel.” Methenamine silver stain. (Figure courtesy of Dr. Lucille Georg, Public Health Image Library, Centers for Disease Control and Prevention.)

Transmission & Epidemiology

This fungus grows in the soil and is endemic in rural Latin America. Disease occurs only in that region.

Pathogenesis & Clinical Findings

The spores are inhaled, and early lesions occur in the lungs. Asymptomatic infection is common. Alternatively, oral mucous membrane lesions, lymph node enlargement, and sometimes dissemination to many organs develop.

Laboratory Diagnosis

In pus or tissues, yeast cells with multiple buds resembling a “ship captain’s wheel” are seen microscopically. A specimen cultured for 2 to 4 weeks may grow typical organisms. Skin tests are rarely helpful. Serologic testing shows that when significant antibody titers (by ID or CF) are found, active disease is present.

Treatment & Prevention

The drug of choice is itraconazole taken orally for several months. There are no means of prevention.

SELF-ASSESSMENT QUESTIONS

1. Regarding coccidioidomycosis and C. immitis, which one of the following is most accurate?

(A) C. immitis is a mold in the soil and a yeast in the body.

(B) The diagnosis of acute coccidioidomycosis can be made by detecting IgM antibodies in the patient’s serum.

(C) Travelers to the Philippines are at high risk of acquiring the disease.

(D) The nodules of erythema nodosum are a typical finding in disseminated coccidioidomycosis.

(E) Infection typically occurs when arthrospores enter the skin (e.g., through a wound caused by a rose thorn).

2. Regarding histoplasmosis and H. capsulatum, which one of the following is most accurate?

(A) In tissue biopsies, H. capsulatum is found as a yeast within macrophages.

(B) The laboratory diagnosis is made by seeing germ tubes when incubated at 37°C.

(C) Histoplasmosis occurs primarily in the tropical areas of Central and South America.

(D) To prevent disease, people who live in endemic areas should receive the vaccine containing histoplasmin.

(E) Most infections are acquired by ingesting food accidentally contaminated with fungal spores from the soil.

3. Regarding B. dermatitidis, which one of the following is most accurate?

(A) It forms a mycelium in culture at 37°C in the clinical lab.

(B) Humoral immunity is the main host defense against this organism.

(C) It causes a dermatophytid (“id”) reaction when it disseminates to the skin.

(D) The most important virulence factor of this organism is endotoxin in its cell wall.

(E) It is a dimorphic fungus that exists as a mold in the soil and a yeast in the body.

4. Your patient is a 30-year-old woman who is in her third trimester of pregnancy, is of Filipino origin, and lives in the Central Valley of California. She complains of severe low back pain of several weeks in duration. An X-ray reveals a lesion in the fourth lumbar vertebra. Material from a needle biopsy of the lesion is examined by a pathologist who calls to tell you the patient has coccidioidomycosis. Of the following, which one did the pathologist see in the biopsy?

(A) Nonseptate hyphae

(B) Septate hyphae

(C) Spherules containing endospores

(D) Yeasts with a single bud

(E) Yeasts with multiple buds

5. Your patient is a 30-year-old man who is human immunodeficiency virus (HIV) antibody positive with a CD4 count of 100. He has an ulcerated lesion on his tongue, and biopsy of the lesion reveals yeasts within macrophages. A diagnosis of disseminated histoplasmosis is made. Which one of the following is the best choice of drug to treat his disseminated histoplasmosis?

(A) Amphotericin B

(B) Caspofungin

(C) Clotrimazole

(D) Flucytosine

(E) Terbinafine

ANSWERS

1. (B)

2. (A)

3. (E)

4. (C)

5. (A)

SUMMARIES OF ORGANISMS

Brief summaries of the organisms described in this chapter begin on page 658. Please consult these summaries for a rapid review of the essential material.

PRACTICE QUESTIONS: USMLE & COURSE EXAMINATIONS

Questions on the topics discussed in this chapter can be found in the Mycology section of PART XIII: USMLE (National Board) Practice Questions starting on page 708. Also see PART XIV: USMLE (National Board) Practice Examination starting on page 731.